Alkyl esters of 3-(3,4-dihalogenophenyl)-2,6-dioxopiperidine-3-propionic acid of use as intermediates

ABSTRACT

The invention relates to lower-alkyl esters of 3-(3,4-dihalophenyl)-2,6-dioxopiperidine-3-propionic acid derivatives, and to processes for preparing the same.

The subject matter of the present invention is a lower alkyl ester of3-(3,4-dihalophenyl)-2,6-dioxopiperidine-3-propionic acid. The inventionalso relates to a process for the preparation of this compound and tothe use of said compound in preparing the corresponding acid.

3-(3,4-Dichlorophenyl)-2,6-dioxopiperidine-3-propionic acid is disclosedin Patent Application WO 97/32852. According to this patent application,3-(3,4-dichlorophenyl)-2,6-dioxopiperidine-3-propionic acid can bereduced, for example by borane, to give3-(3,4-dichlorophenyl)-3-(3-hydroxypropyl)piperidine. The lattercompound, disclosed in Patent Application EP-A-673 928, is anintermediate of use in the preparation of osanetant. Osanetant is aspecific antagonist of NK₃ receptors described, in particular, by X.Emonds-Alt in Life Sci., 1995, 56 (1), 27-32.

The novel compound of formula:

in which:

X represents a halogen, preferably a chlorine or fluorine atom;

R₁ represents a linear C₁-C₄ alkyl, preferably a methyl;

has now been found.

The present invention relates very particularly to the compound offormula (I) in which X=Cl and R₁=CH₃.

The invention comprises the compound of formula (I) in the racemic formand in the optically pure form.

The compound of S configuration corresponding to the formula:

in which R₁ and X are as defined above for (I), is particularlypreferred.

According to the present invention, in order to prepare the compound offormula (I), an acid of formula:

in which X is as defined for (I), is esterified. The compounds offormula (III) are disclosed in Patent Application WO 97/32852.

The esterification is carried out by conventional means well known to aperson skilled in the art. For example, by the action of an alcohol inan acidic and anhydrous medium or alternatively by the action of thionylchloride, to prepare the chloride of the acid of formula (III) as anintermediate, and then by the action of an alcohol of formula R₁OH, inwhich R₁ is as defined above for (I).

According to the process of the invention, the optical isomer of formula(II) can be prepared in the optically pure form by a processcharacterized in that an enantioselective enzymatic hydrolysis of thecompound of formula:

is carried out.

Thus, the racemic compound of formula (I) is hydrolyzed by an enzymechosen from lipases, proteases or esterases, lipases or esterases beingpreferred.

Mention may be made, as nonlimiting examples, of lipases or esterases ofCandida cylindracea, Candida rugosa, Pseudomonas flurorescens, Humilicalanuginosa or Candida lipolytica, α-chymotripsin or pig liver esterase.

Preference is given to the esterase or the lipase of Candida rugosa, orof Candida cylindracea, separately or as a mixture.

These enzymes are used in the purified form or in the form of crudeextracts. The enzymes may or may not be attached to a support.

The hydrolysis reaction is carried out according to the followingreaction scheme:

The enzymatic hydrolysis according to the invention is carried out in amedium comprising water and an organic solvent. The organic solvent canbe nonpolar or moderately polar, such as a C₁-C₁₀ ether, a C₁-C₁₀alkane, a C₁-C₁₀ tertiary alcohol, a C₁-C₁₀ ketone, a C₁-C₁₀ sulfoxideor furan, or, in some cases, a chlorinated solvent, such asdichloromethane, these solvents being used pure or as a mixture.

Preferably, use is made of a C₁-C₁₀ aliphatic ether, very particularlyof methyl tert-butyl ether.

The water necessary for the hydrolysis can be dissolved in the reactionmedium by a polar cosolvent or alternatively, preferably, the waterconstitutes a separate phase, the hydrolysis reaction then being carriedout in a two-phase medium.

Thus, it is very particularly preferable to carry out the reaction in atwo-phase medium composed of methyl tert-butyl ether (MTBE) and water.The MTBE/water ratio can vary from 1/99 to 99/1; a ratio of the order of40/60 to 50/50, very particularly 44/56, is preferred.

The water used can be buffered or unbuffered and its pH can vary from 4to 10 approximately; use is preferably made of water with a pH of theorder of 5 to 8.

The concentration of diester in the reaction medium can vary in theproportions [lacuna] 1 to 500 g/l and preferably from 1 to 150 g/l,where the amount of enzyme varies in proportions from 0.0001 to 150 g/land preferably from 1 to 50 g/l.

The temperature of the enzymatic hydrolysis reaction can vary between 0°C. and +50° C. and preferably between +16° C. and +35° C.

The duration of the reaction is between 3 hours and 36 hours, generallyin the region of 10 hours.

The chiral ester of formula (II) is isolated by extraction, after havingprecipitated and then filtered off the enzyme used.

According to the present invention, a compound of formula (II) can alsobe prepared by a process consisting in carrying out a cyclization of thecompound of formula:

in which R₁ and X are as defined above for (I).

The cyclization of the compound of formula (VI) is carried out eitherthermally or in the presence of a catalyst.

Thus, a thermal cyclization can be carried out between 170° C. and 250°C., either in a molten medium or in the presence of a solvent, forexample an inert solvent, such as toluene, DMSO, sulfolane or tetralin.The thermal cyclization is preferably carried out in a molten medium ata temperature in the region of 200° C.

The cyclization can also be carried out in the presence of a catalyst,such as an acid anhydride, for example acetic anhydride, phosphoruspentoxide, triflic anhydride, trifluoroacetic anhydride ormethanesulfonic anhydride, or an acid, such as methanesulfonic acid ortriflic acid, or a mixture of an acid anhydride and of an acid.

It is preferable to use, as catalyst, methanesulfonic anhydride andmethanesulfonic acid or triflic anhydride and triflic acid.

The cyclization reaction is carried out at a temperature of between 20°C. and 130° C., preferably between 70° C. and 120° C.

Catalytic cyclization, which makes it possible to retain the opticalpurity, is preferably used in carrying out the cyclization of thecompound of formula (VI).

The compound of formula (II) is isolated from the medium by extractionusing conditions known to a person skilled in the art.

The compound of formula (VI) is obtained by a process consisting intreating, by an enzyme, a compound of formula

in which R₁ and X₁ are as defined above for (I).

The preparation of a compound of formula (V) is disclosed in PatentApplications EP-A-673 928 and WO 97/32852.

To convert the racemic diester of formula (V) to the chiral hemiester offormula (VI), an enantioselective enzymatic hydrolysis is carried outwhile choosing conditions similar to those described above.

The chiral hemiester of formula (VI) is isolated from the medium eitherby selective extraction or by precipitation after acidification of theaqueous phase.

The compound of the formula (VI) is novel and constitutes a furtheraspect of the present invention.

According to a further aspect, the present invention relates to the useof a compound of formula (II) in the preparation of a compound offormula:

in which X is as defined above;

the hydrolysis of an ester of formula (II) being carried out underconditions which make it possible to retain the stereochemistry of the3-carbon of the piperidinedione. Thus, use may be made of the action ofan acid, for example the action of a carboxylic acid in the presence ofan inorganic acid, preferably acetic acid in the presence ofhydrochloric acid.

Thus, the present invention relates to a process for the preparation ofa compound of formula (VII) by hydrolysis of an ester of formula (II).

According to another aspect, the present invention relates to the use ofa compound of formula (II) in the preparation of a compound of formula:

The reduction of the compound of formula (II) to a compound of formula(VIII) can be carried out by the action of a reducing agent.

The reducing agents used are borane complexes, such as, for example,borane-tetrahydrofuran or borane-dimethyl sulfide, or alternatively amixed alkaline hydride, such as lithium aluminum hydride or sodiumbis(2-methoxyethoxy)aluminum hydride in solution in toluene (Red-Al®).These reductions take place without racemization; the preferred reducingagent is the borane-tetrahydrofuran complex.

The reduction with borane is carried out in a solvent, preferably anaprotic solvent, such as tetrahydrofuran, at the reflux temperature ofthe solvent. The reduction is generally complete after heating for 1 to6 hours and the 3,3-disubstituted piperidine is isolated according toconventional methods, the excess borane first being destroyed withmethanol. The free base can be isolated by evaporation of the solventand then the residue is taken up in water, acidification is carried outwith hydrochloric acid, treatment is carried out with a base, preferablysodium hydroxide, and extraction is carried out with a solvent.

The free base of formula (VIII) can be converted to one of its saltsaccording to well known techniques. The borane used for the reductioncan be generated in situ according to conventional methods.

Thus, the present invention relates to a process for the preparation ofa compound of formula (VIII) by reduction of a compound of formula (II).

Finally, according to another aspect, the present invention relates tothe use of a compound of formula (VI) in the preparation of a compoundof formula:

in which X is as defined above for (I), by reduction in the presence ofan alkaline hydride, such as, for example, LiAlH₄ or LiAlH₃ in methanol.

A compound of formula:

is prepared by cyclization of the compound of formula (IX) under theconditions described above.

The compound of formula (IX) is novel and forms part of the invention.

The compound of formula (X) is disclosed in International PatentApplication WO 98/05640.

Thus, the present invention relates to a process for the preparation ofa compound of formula (IX) by reduction of a compound of formula (VI).

In the present description, the following abbreviations are used:

DMSO: dimethyl sulfoxide

MTBE: methyl tert-butyl ether

TFH: tetrahydrofuran

iso ether: isopropyl ether

AT: ambient temperature

HPLC: high pressure liquid chromatography

IR: infrared

NMR: nuclear magnetic resonance at 250 or 300 MHz

δ: chemical shift, expressed in ppm

s: singlet; d: doublet; d of d: doublet of doublet;

m: multiplet or unresolved peak.

The following examples illustrate the invention.

EXAMPLE 1 Methyl Ester of3-(3,4-Dichlorophenyl)-2,6-dioxopiperidine-3-propionic Acid

33 g of 3-(3,4-dichlorophenyl)-2,6-dioxopiperidine-3-propionic acid areplaced in 300 ml of methanol and 1.5 g of H₂SO₄ in a 500 mlround-bottomed flask and then the mixture is heated at reflux for 45minutes. The methanol is evaporated and then the residue is taken up in300 ml of ether and stirred for 2 hours at AT. The precipitate formed isfiltered off, rinsed with iso ether and then dried under vacuum at 40°C. 29.6 g of the expected ester are obtained. Yield 86%.

NMR (DMSO) (solvent δ ¹H: 2.5 ppm) δ: 11 (s, 1H); 7.26-7.65 (m, 3H);3.51 (s, 3H); 2.06-2.51 (m, 8H). EXAMPLE 2

Methyl Ester of 3-(3,4-Dichlorophenyl)-2,6-dioxopiperidine-3-propionicAcid, (+) Isomer

(Process 1)

5 g of Candida cylindracea L034 lipase (Biocatalysts), in suspension in25 ml of 0.1M pH 7.0 phosphate buffer, are added to 1 g of methyl esterof racemic 3-(3,4-dichlorophenyl)-2,6-dioxopiperidine-3-propionic acidin 20 ml of MTBE (50 g/l). The reaction mixture is thermostaticallycontrolled at 40° C. and stirred for 5 hours. The progress of thereaction is monitored by HPLC. After reacting for 5 hours, 48% of thestarting material is hydrolyzed; the reaction is halted. 80 ml of MTBEare added to the reaction mixture and the latter is placed in ice, and90 ml of acetone are incorporated in order to precipitate the enzyme.The precipitate is filtered off on a cellulose filter and then theorganic solvents are evaporated. 2 equivalents of triethylamine areadded to the remaining aqueous phase in order to bring the pH of themedium to 8.5. The non-hydrolyzed ester is extracted with 3×25 ml ofdichloromethane. The dichloromethane phase is dried over anhydrousmagnesium sulfate. After filtering and evaporating the dichloromethaneto dryness (under vacuum), 500 mg of a yellow gum are isolated,corresponding to the expected compound (purity 96% by HPLC analysis).Extraction to an acidic pH is subsequently carried out. 25 ml ofdichloromethane and 2 ml of 1N H₂SO₄ are added to the aqueous phase,with stirring and then extraction is carried out twice with 25 ml ofdichloromethane. The organic phase is dried over anhydrous magnesiumsulfate, filtered and evaporated to dryness under vacuum. 450 mg ofwhite solid are obtained, analyzed by HPLC: 100% of3-(3,4-dichlorophenyl)-2,6-dioxopiperidine-3-propionic acid, (−) isomer.

NMR (DMSO) (solvent δ ¹H: 2.5 ppm):3-(3,4-Dichlorophenyl)-2,6-dioxopiperidine-3-propionic acid, (−) isomer:δ: 12.10 (s, 1H); 11.0 (s, 1H); 7.66 (d, 1H); 7.55 (d, 1H); 7.28 (dd,1H), 2.50-2.40 (m, 2H); 2.25-2.0 (m, 6H).

Expected compound:

δ: 11.0 (s, 1H); 7.66 (d, 1H); 7.55 (d, 1H); 7.28 (dd, 1H), 3.52 (s,3H); 2.50-2.40 (m, 2H); 2.35-2.0 (m, 6H)3-(3,4-Dichlorophenyl)-2,6-dioxopiperidine-3-propionic acid, (−) isomer.α_(D) ²⁰=−105 (c=0.25, methanol).

Expected compound: α_(D) ²⁰=+119 (c=0.25, methanol).

EXAMPLE 3 Methyl Ester of3-(3,4-Dichlorophenyl)-2,6-dioxopiperidine-3-propionic Acid, (+) Isomer

(Process 2)

A)

Monomethyl Ester of 4-Cyano-4-(3,4-dichlorophenyl)-heptanedioic Acid,(−) Isomer

To 12 g of dimethyl ester of 4-cyano-4-(3,4-dichlorophenyl)heptanedioicacid are dissolved in 53 ml of MTBE and 1 g of Candida cylindracea L034lipase (Biocatalyst) are dissolved in 66 ml of 50 mM pH 7 phosphatebuffer. The two solutions are mixed in a 500 ml three-neckedround-bottomed flask. The reaction mixture is stirred vigorously, so asto create an emulsion. The temperature is set at 20° C. The reaction ishalted after 5 hours. The progress of the reaction is monitored by HPLC.

The monomethyl ester is separated as follows: 240 ml of acetone areadded to the reaction mixture and the medium is placed at 5° C. for 2hours in order to precipitate the lipase. After 2 hours, the precipitateis filtered on a cellulose filter. The organic solvents are evaporatedfrom the liquid phase under reduced pressure. The resulting aqueousphase is basified to pH 9 (NaHCO₃) and extracted with toluene (240 ml).The toluene phase is evaporated to dryness. This results in a powdercomprising 90% of starting dimethyl ester and 10% of expected monomethylester. The aqueous phase is acidified to pH 2.5 (1N HCl) and thenextracted with CH₂Cl₂ (240 ml). After evaporating, the expectedmonomethyl ester is isolated in the form of a white powder: 7.8 g.Purity: 99%.

The monomethyl ester can also be separated in the following way:

At the end of the reaction, the mixture is basified at pH=9 by additionof sodium hydroxide and then the aqueous phase and the organic phase areseparated by settling. The organic phase is acidified up to pH=2.5 byaddition of HCl. A precipitate which corresponds to the hemiester isformed and is recovered by filtration.

The hemiester can be purified by recrystallization from acetonitrile.

Percentage analysis: C H N Theory 52.34 4.32 4.06 Measured 52.24 4.334.10

Melting point: 110.2° C. IR (nujol) : 2238 cm⁻¹ (nitrile); 1740 cm⁻¹(ester), 1693 cm⁻¹ (carboxylic acid); NMR (DMSO): δ; 12.30 (s, 1H); 7.73(d, 1H); 7.72 (d, 1H); 7.46 (dd, 1H); 3.51 (s, 3H); 2.40-2.28 (m, 4H);2.35 (m, 1H); 2.25 (m, 1H); 2.07 (m, 1H); 1.95 (m, 1H); ¹³C NMR (DMSO):δ: 173.3, 172.2, 138.3, 132.5, 131.7, 131.6, 128.6, 127.2, 121.1, 52.0,47.0, 34.8, 34.7, 30.5, 30.3; α_(D) ²⁰=1.2 (c=1, MeOH).

B)

Methyl Ester of 3-(3,4-Dichlorophenyl)-2,6-dioxopiperidine-3-propionicAcid, (+Isomer)

1 g of the compound of stage A is introduced into a sealable Pyrex tube.The tube is placed under vacuum (water pump) and then sealed and broughtto a temperature of 250° C. After reacting for 5 hours, the tube iscooled to ambient temperature and opened. The reaction product isdissolved in 6 ml of THF. After evaporating to dryness (under vacuum),the residue is dissolved in 50 ml of dichloromethane and the organicphase is washed with 3×50 ml of a 1M aqueous NaHCO₃ solution. Afterdrying over anhydrous MgSO₄ and evaporating the dichloromethane undervacuum, 700 mg of expected compound are isolated in the form of a yellowoil (purity 94%, HPLC). The product is recrystallized from isopropylether (yield: 70%).;

Melting point: 105.5° C. α_(D) ²⁰=+62 (c=1, methanol/THF; 188/12; v/v).

Methyl Ester of 3-(3,4-Dichlorophenyl)-2,6-dioxopiperidine-3-propionicAcid, (+Isomer)

This compound can also be prepared by heating in the presence ofmethanesulfonic acid anhydride according to the process described below.

1 g of methanesulfonic acid anhydride and 60 mg of methanesulfonic acid(100%) are introduced into a 100 ml three-necked flask under a nitrogenstream. The mixture is heated until it melts. 1 g of the compound ofstage A is added to the reaction medium and the combined mixture isbrought to 100° C. The reaction is monitored by thin layerchromatography (CH₂Cl₂: MeOH, 95.5). After one hour, the reaction ishalted. The medium is cooled to ambient temperature and the anhydride ishydrolyzed by the addition of water. The reaction product is extractedwith dichloromethane and purified by washing with a 1M aqueous NaHCO₃solution. After drying over anhydrous MgSO₄ and evaporating thedichloromethane under vacuum, the glutaramide ester is isolated in theform of a yellow oil. The expected product crystallizes slowly whileexposed to the air: 0.85 g is obtained (HPLC analysis: chemical purity98%). Melting point 105° C.

α_(D) ²⁰=+118° C. (c=0.25, methanol).

The thermal cyclization reaction takes place partially with racemizationin comparison with the catalyzed cyclization reaction.

EXAMPLE 4 3-(3,4-Dichlorophenyl)-3-(3-hydroxypropyl)-piperidine Fumarate

17.2 g of methyl ester of3-(3,4-dichlorophenyl)-2,6-dioxopiperidine-3-propionic acid aredissolved in 50 ml of THF under nitrogen. 200 ml of 1M borane in THF areadded over 10 minutes at 10° C. After heating at reflux for 2 hours, anadditional 60 ml of 1M borane in THF are added and heating is maintainedat reflux for a further 1 hour. The excess borane is destroyed withmethanol. After significant evolution of gas, the mixture is heated atreflux for 30 minutes and then the solvents are evaporated. The residueis taken up in 300 ml of water and 10 g of H₂SO₄ and then the mixture isheated at reflux for 2 hours and left overnight at AT. 25 ml ofconcentrated sodium hydroxide solution are added and then extraction iscarried out (twice) with 80 ml of butanol. The organic phase is washedwith 1000 ml of water and then concentrated, and the residue is taken upin 100 ml of isopropanol. Heating is carried out at reflux, salificationis carried out by addition of 7 g of fumaric acid in 75 ml ofisopropanol and the mixture is allowed to return to AT. The precipitateformed is filtered off and then dried under vacuum. 13.23 g of theexpected compound are obtained.

The filtrates are concentrated and an additional 0.70 g of the expectedcompound is isolated. Overall yield: 81.5%.

EXAMPLE 5 3-(3,4-Dichlorophenyl)-2,6-dioxopiperidine-3-propionic AcidMethyl Ester of 3-(3,4-dichlorophenyl)-2,6-dioxopiperidine-3-propionic[Lacuna], (+) Isomer

This compound is prepared in Example 3, stage C.

B) 3-(3,4-Dichlorophenyl)-2,6-dioxopiperidine-3-propionic Acid

0.668 g of the compound of the preceding stage, 2 ml of acetic acid and0.10 ml of concentrated hydrochloric acid are introduced into a 100 mlthree-necked flask. The combined mixture is heated to 70° C. After 2hours, the reaction product precipitates and the reaction is halted.After returning to ambient temperature, 2 ml of water are added to thereaction medium. The reaction product is filtered off on a sinteredglass filter, washed with water and then recrystallized from aceticacid. 0.47 g of the expected compound is obtained. (Yield 70%).

α_(D) ²⁰=+117 (c=0.25, methanol).

EXAMPLE 6 4-Cyano-4-(3,4-dichlorophenyl)-7-hydroxyheptanoic Acid

231 mg of LiBH₄ and 30 ml of MTBE are introduced under a nitrogen streamand then 429 μl of methanol, diluted in 30 ml of MTBE, are addeddropwise. 1 g of compound prepared in Example 3, stage A, in solution in80 ml of MTBE ether, is added to the reaction medium and the combinedmixture is heated at reflux. After three hours, the reaction medium isplaced in ice and a 1N HCl solution is added. When there is no longerevolution of gas, the reaction product is extracted withdichloromethane. After drying over anhydrous magnesium sulfate andevaporating the solvent under vacuum, the product is isolated in theform of a white gum.

The product is recrystallized from 6 ml of toluene and 600 mg of anexpected compound are obtained in the form of a white powder.

α_(D) ²⁰=−10.7 (c=1, methanol). NMR (DMSO) (solvent δ ¹H: 2.5 ppm): δ:12.30 (bs, 1H) ; 7.69 (d, 1H) ; 7.65 (d, 1H) ; 7.42 (dd, 1H); 4.5 (bs,1H); 3.33 (t, 2H); 2.35-2.2 (m, 3H); 2.1-1.8 (m, 3H); 1.50-1.10 (m, 2H).

What is claimed is:
 1. A compound of formula:

in which: X represents a halogen, R₁ represents a linear C₁-C₄ alkyl. 2.A compound according to claim 1 of formula (I), in which X represents achlorine atom or a fluorine atom.
 3. A compound according to claim 1 offormula (I), in which X=Cl and R₁=CH₃.
 4. A compound according to claim1 of S configuration corresponding to the formula:

in which R₁ and X are as defined for (I) in claim
 1. 5. A process forthe preparation of a compound according to claim 1 wherein an acid offormula:

in which X is as defined for (I) in claim 1, is esterified.
 6. A processfor the preparation of a compound according to claim 4 which comprisescarrying out a cyclization of the compound of formula:

in which R₁ and X are as defined for (I) in claim
 1. 7. A processaccording to claim 6 wherein the cyclization is carried out either in amolten medium between 170° C. and 250° C. or in the presence of acatalyst between 20° C. and 130° C.
 8. A process according to claim 7wherein the cyclization is carried out in a molten medium at atemperature in the region o 200° C.
 9. A process according to claim 7wherein the cyclization is carried out in the presence of an acidanhydride or of an acid, or of a mixture of an acid anhydride and of anacid.
 10. A process according to claim 9 wherein the cyclization iscarried out in the presence of methanesulfonic anhydride and ofmethanesulfonic acid or in the presence of triflic anhydride and oftriflic acid.
 11. A compound according to claim 4 wherein X represents achlorine atom or a fluorine atom.
 12. A compound according to claim 11wherein X=Cl and R₁=CH₃.